The method of obtaining derivatives of 2-anilinopyrimidines or their acid additive salts

 

(57) Abstract:

Usage: in the chemical industry as a method of obtaining derivatives of 2-anilinopyrimidines, compounds with fungicidal activity. The invention is a method of obtaining derivatives of 2-anilinopyrimidines General formula 1 where R1- H, halogen; R2- H, halogen, methyl; R3- alkyl - C1-C4substituted by halogen, alkyl (C1-C4), cyclopropyl; R4- cyclopropyl, unsubstituted or substituted by halogen or stands, or their acid additive salts, namely, that the thiourea of formula II S=C(NH2)2or salt Saturnia formula III where Athe anion of the acid, and R5- C1-C8-alkyl or unsubstituted or substituted by halogen and/or C1-C4-alkyl, benzyl enter into interaction with the diketone IV R3-C(O)CH2O(O)-R4the process is conducted in an inert solvent in the presence of acid at 20 to 140 C, to obtain the compounds of General formula V where y is H or R5, R5- C1-C8-alkyl or unsubstituted or substituted by halogen and/or (C1-C4)-alkyl benzyl, the compound V, where y - N in the form of alkaline or alkaline earth salts condense the last oxidized by the oxidizer, as nakilat (natantia acid or over-p-chlorbenzoyl acid or hydrogen peroxide to obtain the pyrimidine compounds of formula VIII which condense with formylamino formula IX in an inert solvent in the presence of a base at (-30) - (120) to obtain the compounds of formula X which is subjected to hydrolysis with a 10 - 110S in the presence of base or acid in water or aqueous mixtures of solvents and the target product is isolated in the free state or in the form of an acid additive salt. table 4.

The invention relates to methods of producing derivatives of 2-anilinopyrimidines or acid additive salts of novel biologically active compounds, which can find application in agriculture.

Known N-pyrimidinedione derivatives effective against damaging plants fungi [1,2] .

However, the known compounds are not active.

The purpose of the invention is the finding in a series of derivatives of 2-anilinopiperidine or their acid additive salts possessing favorable for practical use of biocidal spectrum for combating insects and phytopathogenic microorganisms, in particular fungi.

P R I m e R 1. Getting 2-methylmercapto-4-methyl-6-cyclopropyl - pyrimidine.

To 69,5 g (0.25 mol) sulfate 5-methylisothiazoline and 41 g (0.5 mol) of anhydrous sodium acetate in 375 ml of acetic acid under stirring at room temperature was added dropwise 63 grams (0.5 mole) of 1-cyclopropyl-1,3-butanedione for 10 min and immediately thereafter heated for 14 h at the boiling point of phlegmy. After cooling to room temperature, filtered and the resulting product is then washed with glacial acetic acid. The filtrate is evaporated on a rotary evaporator and the remaining brown oil with stirring, poured into 600 ml of water. After double extraction with methylene chloride, extracted portions of 200 ml, the extract is evaporated on a rotary evaporator and the remaining oil distil in high vacuum, BP. 81-82aboutWith/30 PA. Output to 64.8 g (of 0.36 mol; output from theory 72% ).

P R I m m e R 2. Polucheniya dissolved in 100 ml of acetic acid under stirring at 0aboutC for 1 h, mixed with 28,3 g (0.25 mol) of 30% hydrogen peroxide 1 h after the addition is heated to the reaction solution for 2 h to 70aboutC, cooled to room temperature and with stirring, poured into 800 ml of ice water. Precipitated white crystals are filtered and melted at 74-76aboutAfter drying.

P R I m e R 3. Obtaining 2-(4-chlorpheniramine)-4-methyl-6 - cyclopropylamino.

of 15.5 g (0.1 mol) of 4-chlorpromazine in 300 ml of toluene under stirring at room temperature is mixed with 4.4 g (of 0.11 mol) of a 60% dispersion of sodium hydride. After heating for 1 h to 100aboutWith cooled to room temperature and add to 20.1 g (0,095 mole) of 2-methylsulphonyl-4-methyl-6-cyclopropylamino with stirring for 1 h After stirring for 5 h, washed with 100 ml of water, dried toluene solution over sodium sulfate, filtered and the solvent evaporated. The brown residue is dissolved in 300 ml of ethanol and at room temperature for 10 min, mixed with 60 ml of 10% aqueous sodium hydroxide solution and stirred for 3 h at room temperature. After evaporation of the ethanol, the residue with stirring, poured into 300 ml water and three times extracted with diethyl effrot and evaporate the ether. The remaining dark brown oil is cleaned by columnar chromatography through silica gel (eluent toluene/chloroform/diethyl ether 4,2,1). After evaporation of the eluting mixture yellowish oil crystallized, triturating with petroleum ether (50-70aboutC). Light yellow crystals melting at 86-87aboutC.

Similarly can be obtained the compounds listed in table. 4.

Obtaining salts of the compounds according to the invention.

P R I m e R 4. Getting 2-phenylamino-4-methyl-6 - cyclopropylamino-phosphate.

4 g (18 mmol) of 2-phenyl-4-methyl-6-cyclopropyl-pyrimidine in 250 ml of absolute diethyl ether at room temperature with rapid stirring for 10 min on drops mixed with 2,19 g (19 mmol) of 85% ortho-phosphoric acid (H. D.). The resulting white precipitate is filtered and optionally washed with 20 ml of absolute diethyl ether. White crystals melt at 188-191aboutC. the Yield 5.6 g (17.3 mmol: = 96% of theory).

Getting 2-phenylamino-4-methyl-6-cyclopropyl-primogeniture

NH HNO312 g (53 mmol) of 2-phenylamino-4-methyl-6 - cyclopropylamino in 180 ml of absolute diethyl ether at room temperature and at a fast Pisa white precipitate is filtered and optionally washed with 20 ml of absolute diethyl ether. White, slightly beige crystals melt at 151-153aboutWith decomposition; output: 14,7 g (52 mmol: = 96% of theory).

Similarly, methods of preparing these salts

NH HCl So pl. 151-154aboutWITH

NH H2SO4So pl. 183-185aboutWITH

NH1/2H2SO4So pl. 200-202aboutWITH

The biological tests of the obtained compounds

2.1. Action against Botrytis cinerla on apples.

Artificially damaged apples are treated by the fact that lesions dotted prepared from wettable powder of the active substance broth for spraying(0,02% , 0,006% , 0,002% , 0,0006% the active substance). The treated fruits are then inoculant spore suspension of the fungus and during the week incubated at high humidity at about 20aboutC. When evaluating calculate rotten lesions and from this deduce the fungicidal action of the test substance.

Comparative way, untreated, but infected control plants show defeat Botrytis = 100% .

2.2. Action against Veuturia niagulis on Apple shoots.

Apple cuttings with fresh shoots length of 10-20 cm are sprayed prepared from a wettable powder Biologicheskie infect plants with a suspension of conidia of the fungus. The plants are then incubated for 5 days at a relative humidity of 90-100% in the next 10 days is kept in a greenhouse at 20-24aboutC. Defeat scab evaluated 15 days after infection.

Comparative way, untreated, but infected control plants show defeat = 100% . 3. Evaluation scale: evaluationx)% activity 1 95 (full action) 3 80-95 (accepted

action) 6 50-80 (insufficient dei

due) 9 50 (no steps)

x)evaluation with intermediate values are averages of results from multiple experiments.

The results are shown in table. 1.

Description of the experience.

Comparison of the activity of biologically active substances of this application with those of the prior art.

1. Connection /PS /5-16701/1+2/+E/

X1NH Connection 1.1

X2NH Connection 1.14

X3NH Connection 1.59

X4NH Connection 1.33

X5NH Connection 1.73

Y1NH European

patent 224339

the connection 37

Y2NH European

patent 224339

the connection 36

2. Implementation experience.

2.1. Action against Botrytis cinerea on apples.

aboutC. When evaluating calculate rotten lesions and from this conclude fungicidal action of the test substance.

Comparative way, untreated, but infected control plants show defeat Botrytis = = 100% .

2.2. Action against Venturia inaegualis on Apple shoots.

Apple cuttings with fresh shoots length of 10-20 cm are sprayed prepared from wettable powder of biologically active substances broth for prisciani (0,006% of active substance). After 24 hours the treated plants infect suspension of conidia of the fungus. The plants are then incubated for 5 days at a relative humidity of 90-100% and over the next 10 days is kept in a greenhouse at 20-24aboutC. Defeat scab evaluated 15 days after infection.

Comparative way, untreated, but infected control plants show defeat = 100% .

2.3. Action against Erysiphae graminis on barley.

Height of approximately 8 cm of the barley plants are sprayed prepared the CTV). After 3-4 hours the treated plants opilivayut conidia of the fungus. The infected barley plants kept in a greenhouse at about 22aboutAnd 10 days later evaluate the defeat of the mushroom.

Comparative way, untreated, but infected control plants show defeat = 100% . 3. Evaluation scale evaluationx) % activity 1 95 (full action) 3 80-95 (accepted

action) 6 50-80 (low

action) 9 50 (no dei-

of)

x)Evaluation with intermediate values are averages of results from multiple experiments.

4. The results are shown in table. 2.

P R I m e R 5. Action against Helmi uthosporium gramineum.

Wheat was soaked with a spore suspension of the fungus and again dried. Soaked grain protravlivanie obtained from a wettable powder suspension of the test substance (600 million-1the active substance, considering the weight of the seeds). After two days of grain was placed on the appropriate agrarian plates and four days later evaluated the development of colonies of the fungus around the grain. The number and size of colonies of the fungus were used for evaluation of the test substance. Table joins greatly hinder the defeat grieco after germination within 2 weeks sprayed with a broth for spraying, made from wetting powder biologically active substance (concentration of 0.002% ). After 2 days, the plants were infected with a spore suspension (1.5 x 105spores/ml) of the fungus and incubated for 36 h at 23aboutC and high humidity. Incubation was then continued at normal humidity and a temperature of about 22-23aboutC. Defeat the fungus was assessed 8 days after infection. Untreated, but infected control plants were affected by the fungus 100% .

Compounds of table. 4 have shown good efficacy and prevented an extensive lesion of the disease. Defeat the fungus was reduced to 20% or less.

P R I m e R 7. a) contact action against Nepho tettix cineticeps u Nilaparvate leegeus (Hipughen).

The test was carried out on germinated rice plants. For this were planted in pots (diameter 5.5 cm) respectively for 4 plants (14-20 days) with a height of about 15 cm

The plants were sprayed on a rotating plate 100 ml of the prepared aqueous suspension containing 400 million-1the biological active substances. After drying spattered layer on each plant was planted on 40 nymphs (larvae) of the test animals at the third stage of development. To prevent the spread of the CEC is C 6 days nymphs reached the stage of development of adults on the treated plants. Assessment of destruction in percent was carried out 6 days after planting nymphs. The experiment was carried out at approximately 27aboutC, 60% relative humidity and the period of illumination 16 PM

b) systemic action against Nilaparvate lugeus (water). The rice plants about 10 days of age (height 10 cm) were placed in plastic cups, which contained the finished water emulsion to be tested biologically active substances with a concentration of 100 min-1and were closed with a plastic lid with a hole in it. The root of rice plants through a hole in the plastic lid was placed in the prepared test solution. Then on the rice plants were planted on 20 nymphs (larvae Nilaparva telugens) under development N2and N3and closed plastic cylinder. The experiment was carried out at approximately 26aboutC and 60% relative humidity with a period of light 16 hours five days was evaluated destroyed the test animals compared to the untreated control. Thus, it was found that the biologically active substance flowing through the root, striking animals on the upper parts of plants.

Compounds of table. 1 have shown in the text a) and test (b) strongly is soedinenii 1.1, 1.6, 1.14, 1.59, 1.66, 1.87, 1.94, 1.108 and 1.236 was achieved almost complete destruction (98-100% ).

In table. 3 provides data on toxicity, confirming that the obtained compounds are of low toxicity.

The tests showed that the compounds according to the invention have low toxicity, have high fungicidal activity at different photogenic, in addition, they possess high insecticidal activity. (56) U.S. Patent N 3978055, C 07 D 239/42, 1976.

Bayer H. , Hatsehll L. Uber Thiazole XL. Thyazolil (2) - pyrimidijl - (2) - amine. Berichte, 1962, 95, 902-6.

The method of obtaining derivatives of 2-anilinopyrimidines General formula I

NH

where R1is hydrogen or halogen;

R2is hydrogen, halogen, or methyl;

R3- C1-C4-alkyl substituted by halogen, C1-C4is alkyl or cyclopropyl;

R4- cyclopropyl or substituted 1 to 3 times by halogen or stands cyclopropyl,

or their acid additive salts, characterized in that the thiourea of formula II

S= C

or salt tironi General formula III

< / BR>
where A is the anion of an acid;

R5-C1-C8- alkyl or is not substituted or substituted with halogen and/or C1-C4the alkyl benzyl,

enter into interaction value in an invert solvent in the presence of acid at 20 to 140oWITH

obtaining compounds of General formula V

YS

where Y is H or R5,

and the compound of General formula V,

where Y is H, either directly or in the form of alkaline or alkaline earth salt is condensed with the compound of the formula VI

Z - R5,

where Z is halogen,

with the formation of a pyrimidine derivative of the formula VI where Z-R5last oxidized by an oxidant such as natantia nagkalat, over-p-chlorbenzoyl acid or hydrogen peroxide, to obtain the pyrimidine compounds of General formula VII

R5-SO

which condense with formylamino General formula VIII

NHCHO

in an inert solvent in the presence of a base at -30 - 120oWith obtaining compounds of General formula IX

< / BR>
where R1- R4- have the specified values,

which is subjected to hydrolysis with a 10 - 110oIn the presence of base or acid in water or in a mixture of water and solvent and the desired product is isolated in free form or in the form of an acid additive salt.

Priority signs

28.09.87 when R3- C1- C4-alkyl not substituted or substituted with halogen.

11.04.88 when R3

 

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8 cl, 16 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I with PGl2 receptor agonist activity. In formula R1 and R2 represent independently optionally substituted phenyl; Y represents N, N-O or CR5; Z represents N or CR6; A represents NR7; D represents alkylene or alkenylene; or A and D may together form divalent group; E represents phenylene or direct bond, or D and E may together form divalent group; G represents O, S, SO, SO2; R3 and R4 represent hydrogen atom or alkyl; Q represents carboxyl, alkoxycarboxyl, tetrazolyl, carbamoyl or -CONH-SO-R10 group. Prostaglandin I2(PGl2) is potent inhibitor of platelet aggregation and may be effectively used in treatment of vascular diseases, arteriosclerosis, hypertension, etc.

EFFECT: new compounds and drugs for platelet aggregation inhibition and treatment of vascular and other diseases.

15 cl, 3 tbl, 109 ex

FIELD: organic chemistry, chemical technology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a novel method that can be used in industry for synthesis of substituted aniline compound represented by the following general formula (6):

wherein in the general formula (6) each R1, R2 and R3 means independently alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group, alkylcarboxamide group, nitro-group, aryl group, arylalkyl group, aryloxy-group, halogen atom or hydrogen atom; each X and Y means independently hydrogen atom, alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group or halogen atom. Method involves oxidation of substituted indole compound represented by the following general formula (3):

(wherein values R1, R2, R, X and Y are given above) resulting to opening indole ring to yield acetanilide compound represented by the following general formula (4):

(wherein values R1, R2, R3, X and Y are given above) and Ac means acetyl group, and treatment of this compound by reduction and deacetylation. Also, invention relates to novel intermediate compounds. Proposed compound (6) can be used as intermediate substance for production of chemicals for agriculture and as medicinal agents.

EFFECT: improved method of synthesis.

20 cl, 1 sch, 3 tbl, 31 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing inhibitory effect on activity of dipeptidyl peptidase IV (DPP IV) that can be used, for example, in treatment of diabetes mellitus type 2. In compounds of the formula (I) X means nitrogen atom (N) or -C-R5; R1 and R2 mean independently hydrogen atom, (C1-C6)-alkyl; R3 means saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, or perfluoro-(C1-C6)-alkyl; R4 means (lower)-alkyl, (lower)-alkoxy-, (lower)-alkylthio-group, saturated or aromatic 7-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-, amino-group or perfluoro-(C1-C6)-alkyl, 4-fluorophenyloxy-(C1-C6)-alkyl or (C3-C6)-cycloalkyl; R5 means hydrogen atom or (C1-C6)-alkyl. Also, invention relates to methods for synthesis of compounds of the formula (I), pharmaceutical compositions and their using for preparing medicaments used in treatment and/or prophylaxis of DPP IV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

21 cl, 93 ex

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